1. Field of the Invention
This invention relates to a method of at least partially restoring normal growth and weight gain as well as lean body mass in patients with glucocorticoid excess exhibiting a retarded growth rate or weight loss.
2. Description of Related Art
Insulin-like growth factor I (IGF-I) is a polypeptide naturally occurring in human body fluids, for example, blood and human cerebral spinal fluid. Most tissues and especially the liver produce IGF-I together with a specific IGF-binding protein Both of these molecules are under the control of human growth hormone (GH). Like GH, IGF-I is a potent anabolic protein. See Tanner et al., Acta Endocrinol., 84: 681-696 (1977); Uthne et al., J. Clin. Endocrinol. Metab., 39: 548-554 (1974)). IGF-I has been isolated from human serum and produced recombinantly See, e.g., EP 123,228 and 128,733.
Various biological activities of IGF-I have been identified. Researchers have found that an intravenous bolus injection of IGF-I lowers blood glucose levels in humans. See Guler et al., N. Engl. J. Med.. 317: 137-140 (1987). Additionally, IGF-1 promotes growth in several metabolic conditions characterized by low IGF-I levels, such as hypophysectomized rats (Guler et al., Endocrinology, 118: Supp 129 abstract,), diabetic rats (Scheiwiller et al., Nature, 323: 169-171 (1986)), and dwarf rats (Skottner et al., Endocrinology, 124: 2519-2526 (1989)). The kidney weight of hypophysectomized rats increases substantially upon prolonged infusions of IGF-I subcutaneously. Guler et al., Proceedings of the 1st European Congress of Endocrinology, 103: abstract 12-390 (Copenhagen, 1987). The kidneys of Snell dwarf mice and dwarf rats behaved similarly. van Buul-Offers et al., Pediatr. Res., 20: 825-827 (1986); Skottner et al., supra. An additional use for IGF-I is its administration to improve glomerular filtration and renal plasma flow. See EP 327,503 published Aug. 9, 1989.
Human growth hormone is a single-chain polypeptide consisting of 191 amino acids (molecular weight 21,500). Disulfide bonds link positions 53 and 165 and positions 182 and 189. Niall, Nature, New Biology, 230: 90 (1971). GH is a potent anabolic agent, especially due to retention of nitrogen, phosphorus, potassium, and calcium. Among its most striking effects in hypopituitary (growth hormone deficient) subjects is accelerated linear growth of cartilage resulting in increased stature. Kaplan, Growth Disorders in Children and Adolescents (Springfield, Ill.: Charles C. Thomas, 1964). These effects on bone and the lengthening epiphysis could be a result of increased protein synthesis by GH, suggesting a direct role for hormonal supplementation in growth retardation.
Hypercortisolism in humans, whether from Cushing's disease or chronic glucocorticoid therapy, is associated with a number of negative catabolic effects, including reduced growth velocity (Loeb, N. Eng. J. Med., 295: 547 (1976), McArthur et al., Mayo Cliln. Proc., 47: 318 (1972)) and lean body mass (Munro, in Mammalian Protein Metabolism, eds. Munro and Allison (Academic Press, Inc., New York, 1964), p. 381). Glucocorticoids are known to retard linear growth in normal and hypopituitary children and rats (Soyka et al., J. Clin. Endocrinol. Metab., 25: 469 (1965); Loeb, supra, McArthur et al., supra, Nicholson et al., Neuroendocrinology, 39: 343 (IgB4), Luo and Murphy, Endocrinology, 125: 165 (1989)).
The potential of anabolic proteins, such as GH and IGF-I, to counteract the tissue wasting and statural deficits that attend chronic glucocorticoid exposure is poorly understood. There appear to be multiple sites of glucocorticoid action on the endocrine axis governing linear growth. Dexamethasone enhances GH release in vitro (Wehrenberg et al., Science, 221: 556 (1983)), and in vivo (Oosterom et al., Endocrinology, 113: 735 (1983)). Yet, dexamethasone reduces GH-induced IGF-I mRNA and has variable effects on serum IGF-I concentrations In vivo (Luo and Murphy, supra).
A putative IGF-I inhibitor has been identified in children treated with glucocorticoids. Glucocorticoids cause a diabetes-induced rise in the level of IGF-I inhibitor found in the rat. Hofert et al., Metabolism, 38: 594 (1989).
Recently, investigators have reported that IGF-I prevents glucocorticoid-induced weight loss; however, IGF-I treatment did not affect kidney weight. Fagin et al., Endocrine Soc. Annual Meeting Abstract No. 1666 (June 1989).
It is an object of the present invention to provide an agent that at least partially reverses the retardation of growth in normal and hypopituitary children that accompanies chronic treatment with glucocorticoids or Cushing's disease.
It is another object to provide a drug that at least partially counteracts the retardation in lean body mass of patients with glucocorticoid excess, whether children or adults.
It is a further object to provide an agent that antagonizes the diabetogenic effect and minimizes the osteopenic effects of glucocorticoids in patients undergoing chronic glucocorticoid treatment.
These and other objects will be apparent to those of ordinary skill in the art.